Racial and Ethnic Disparities in Clinical Trial Enrollment Among Women With Gynecologic Cancer

Key Points Question Are there racial and ethnic disparities in clinical trial enrollment among women with gynecologic cancer? Findings In this cohort study of 562 592 women with endometrial, ovarian, or cervical cancer, the odds of clinical trial enrollment were lower among Asian, Black, and Hispanic women compared with White women. Comparisons with the US population demonstrated overrepresentation among White women for all cancer sites, underrepresentation among Asian and Hispanic women for all cancer sites, and varied patterns for Black women depending on cancer site. Meaning These findings suggest that efforts to engage women with gynecologic cancer who are from minoritized racial and ethnic groups are needed to increase their representation in clinical trials.


Introduction
Health care disparities exist within all scopes of medicine and occur along various dimensions, including race and ethnicity, socioeconomic status, geography, and language.Racial and ethnic inequities in gynecologic oncology treatment and outcomes are well-established and deeply entrenched in the social determinants of health, 1 prompting calls to address these gaps in care. 2 Clinical trials, defined as research in which humans are prospectively assigned to 1 or more interventions for the evaluation of health-related effects, 3 are essential for ensuring validity, generalizability, and equity of care, as well as advancing medical knowledge.Recent reports 4,5 suggest that between 6% and 8% of the US adult population with cancer participates in clinical trials, with lower representation of patients from minoritized racial and ethnic groups.[8][9] In a recent review, Barry and colleagues 10 outlined the extent of racial disparities in clinical trial enrollment of patients with gynecologic cancer.Most of the reviewed studies compared observed enrollment in clinical trials identified through ClinicalTrials.govwith expected enrollment derived from population-based, age-adjusted incidence rates.Collectively, women from minoritized racial and ethnic groups were underrepresented in these trials, whereas White women were more likely to be overrepresented across gynecologic cancer types.This work is an important starting point for describing racial and ethnic disparities in clinical trial enrollment of patients with gynecologic cancer; however, studies with an internal comparison group with adjustment for potential confounders are needed to fully understand the complex picture of clinical trial enrollment.Moreover, these studies highlight the need for data sets that include large numbers of women from underrepresented groups.As such, we examined associations of race and ethnicity with clinical trial enrollment among women with gynecologic cancer using the National Cancer Database (NCDB).In addition, we present participation-to-prevalence ratios (PPRs) according to period of diagnosis to evaluate trends in the representation status of underrepresented groups in gynecologic cancer trials.

Data Source
The 2020 Participant User File was obtained from the hospital-based NCDB, 11 a cancer registry capturing 70% of cancers diagnosed in the US.Data include sociodemographic characteristics, tumor characteristics, treatment facility attributes, treatment, and survival outcomes abstracted from patient medical records by Certified Tumor Registrars. 12Data submitted to NCDB undergo rigorous quality checks according to American College of Surgeons standards.This study was exempt from the Ohio State University institutional review board and the need for informed consent because the data were anonymous and publicly available, in accordance with 45 CFR §46.We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for cohort studies. 13

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Disparities in Clinical Trial Enrollment Among Women With Gynecologic Cancer

Clinical Trial Enrollment
We categorized women as enrolled in a clinical trial when response observations were enrolled in an institutional (code 2) or double-blind clinical trial (code 3).Categories of no trial (code 0), other (code 1), other-unproven (code 6), or refused trial (code 7) were categorized as no clinical trial enrollment. 14

Covariates
Race and ethnicity were available as self-reported variables coded by the NCDB.We cross-classified race (American Indian/Alaska Native, Asian, Black, Native Hawaiian/Pacific Islander, White, and other) and ethnicity (Hispanic vs non-Hispanic) to produce the following categories: non-Hispanic Asian (hereafter referred to as Asian), non-Hispanic American Indian/Alaska Native (hereafter referred to as American Indian/Alaska Native), non-Hispanic Black (hereafter referred to as Black), Hispanic ethnicity of any race, non-Hispanic Native Hawaiian/Pacific Islander (hereafter referred to as Native Hawaiian/Pacific Islander), non-Hispanic White (hereafter referred to as White), and non-Hispanic other (hereafter referred to as other).The NCDB does not specify what groups are included in "other race."Detailed information on the categories of race that compose the 6 overarching groups is provided in the eAppendix in Supplement 1.

Statistical Analysis
In the NCDB sample, we used multivariable logistic regression to estimate adjusted odds ratios (ORs) and 95% CIs for associations of race and ethnicity with clinical trial enrollment.Factors included as covariates comprised patient, facility, tumor, and treatment characteristics that have been identified as factors related to clinical trial enrollment among patients with cancer 4 and were available in NCDB.

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Disparities in Clinical Trial Enrollment Among Women With Gynecologic Cancer To evaluate the racial and ethnic composition of patients with gynecologic cancer enrolled in clinical trials (in the NCDB) relative to the racial distribution in the overall cancer-specific population, we calculated the PPR according to period of diagnosis (2004-2011 vs 2012-2019). 15The PPR was calculated by dividing the race-specific percentage of clinical trial participants in the study sample (eg, percentage of NCDB patients with endometrial cancer enrolled in clinical trials who are Black) by the percentage of racial and ethnic groups in the US patient population (eg, percentage of US patients with endometrial cancer who are Black) according to cancer site.We used the Surveillance, Epidemiology, and End Results *Stat program to derive population-based race and ethnicity frequencies for each cancer site.We omitted calculations for American Indian/Alaska Native, Native Hawaiian/Pacific Islander, and other women owing to low numbers.Stratification of the PPR by diagnosis period (2004-2011 vs 2012-2019) was done to qualitatively assess clinical trial enrollment over time.We evaluated only 2 time periods to reduce the potential for small numbers.PPRs less than 0.8 can be interpreted as underrepresentation in clinical trials, PPRs of 0.
We also observed that older age at diagnosis (OR per 5-year increment, 0.89; 95% CI, 0.85-0.94)and having 2 or more comorbidities (OR, 0.56; 95% CI, 0.34-0.95)were associated with lower clinical trial enrollment odds.Area-level characteristics were related to clinical trial enrollment.

Discussion
In this retrospective cohort study of women with gynecologic cancer, we used 2 complementary approaches to evaluate racial and ethnic disparities in clinical trial enrollment.First, we examined clinical trial enrollment odds comparing participation among minoritized women with that of White women, with covariate adjustment.These analyses demonstrated lower clinical trial enrollment odds among Asian, Black, and Hispanic women compared with White women, but no difference in enrollment among American Indian/Alaska Native, Native Hawaiian/Pacific Islander, or other race women.In addition, social determinants of health, including area-level income and education, geographic region, and metropolitan status, along with certain facility characteristics, were associated with clinical trial enrollment.In the second analytic approach, analyses comparing the race-specific prevalence of clinical trial enrollment in the NCDB sample with the race-specific cancer prevalence in the US population with gynecologic cancer revealed interesting patterns.First, regardless of diagnosis period, Asian and Hispanic women with an endometrial, ovarian, or cervical cancer were underrepresented in clinical trials compared with the proportion expected on the of US cancer incidence.White women were either adequately represented or overrepresented for all 3 cancer sites, whereas patterns diverged for Black women: among those with endometrial or cervical cancer, adequate representation or overrepresentation was noted but among those with ovarian cancer, underrepresentation was evident.Together, these analyses provide novel information on the landscape of racial and ethnic disparities in gynecologic cancer treatment.
Prior studies 7,8 examining clinical trial representation among patients with gynecologic cancer have compared observed case counts of racial and ethnic groups from published trials (including In both time periods, Asian and Hispanic women were underrepresented in clinical trials for all 3 cancer sites.Black women with an endometrial or cervical cancer diagnosis were either adequately represented or overrepresented in both time periods, but Black women with ovarian cancer were underrepresented.White women were adequately represented or overrepresented in clinical trials for all 3 cancer sites.Numbers were too low to generate meaningful estimates for American Indian/Alaska Native, Native Hawaiian/Pacific Islander, or other race women. trials registered through ClinicalTrials.gov,Gynecologic Oncology Group-based trials, 9 or National Cancer Institute-sponsored gynecologic cancer treatment trials 16 ) to the expected racial and ethnic count obtained from population-based age-adjusted incidence rates.In support of this body of work, we identified adequate representation or overrepresentation in clinical trials among White women with endometrial, ovarian, or cervical cancers along with underrepresentation of Black patients with ovarian cancers.Our findings that Black women with endometrial or cervical cancers were adequately or overrepresented in clinical trials are in line with the findings of 2 prior studies. 8,16For example, Mattei and colleagues 8 reported that Black women with either a uterine or cervical cancer were proportionately enrolled in precision medicine trials, whereas Mishkin and colleagues 16 similarly noted no enrollment disparities for Black women with uterine or cervical cancer in National Cancer Institute-sponsored treatment trials.However, an evaluation of racial representation in Gynecologic Oncology Group-sponsored clinical trials revealed that enrollment of Black women was 9.8-fold lower than expected for endometrial cancer trials and 4.5-fold lower for cervical cancer trials. 9erall, although our PPR findings indicate that Black women are being enrolled in endometrial and cervical cancer clinical trials at levels proportionate to their distribution in the population, this practice of striving for proportional enrollment is unlikely to culminate in the sample sizes needed to make well-powered conclusions about treatment efficacy within minoritized groups. 17Indeed, recent calls for equitable clinical trial inclusion suggest the need to recruit equal numbers of racial and ethnic groups, such that minoritized groups are overenrolled with respect to their size in the general population.A shift in this direction would allow ideally powered analyses of treatment effects within racial and ethnic groups. 18sparities between Black and White populations in gynecologic oncology have been frequently investigated; however, reports focused on other racial and ethnic groups are less common.Our PPR and logistic regression analyses showing underrepresentation and lower clinical trial enrollment odds of Asian and Hispanic women agree with data published by Mattei and colleagues, 8 where women in these groups were less commonly enrolled to precision oncology trials for ovarian and uterine cancer, with Hispanic women also less likely to be enrolled in cervical cancer clinical trials.
Furthermore, in a review of National Cancer Institute-sponsored gynecologic oncology trials, Hispanic, but not Asian, women were less likely to be enrolled in ovarian, uterine, or cervical cancer clinical trials. 16Because of the low numbers of Native Hawaiian/Pacific Islander, American Indian/ Alaska Native, and other race patients, we were unable to provide meaningful estimates of clinical trial enrollment odds or PPRs for these groups.
Apart from race and ethnicity, other factors associated with clinical trial enrollment included the presence of comorbidities, which was related to lower odds of clinical trial enrollment, in line with prior work. 19Although clinical trials traditionally exclude patients with medical comorbidities under the auspice of patient safety, in 2017 and 2021, the American Society for Clinical Oncology recommended broadening clinical trial eligibility to maximize generalizability. 20,21In addition, older age; living in zip codes with higher income; living in zip codes with lower educational attainment; living in urban, small, or medium sized counties; and treatment in the South, Midwest, and Pacific (compared with the Northeast) were associated with lower clinical trial enrollment.Treatment at an academic or research program or an integrated network cancer program was associated with higher odds of clinical trial enrollment.Most of these associations were expected on the basis of prior literature 22,23 ; however, our finding that women living in areas with higher area-level income were less likely to participate in clinical trials was surprising.It is likely that area-level income also captures unmeasured neighborhood effects underlying this unexpected association.Future studies that also include individual-level income measures will be useful in contextualizing this association.

Limitations and Strengths
Our analyses are limited by the available data within the NCDB, because we lack information on important patient and oncologic characteristics.Certain data that can affect clinical trial enrollment, including trial phase sponsor or funding source, availability of clinical trials, trial treatments (and PPRs according to race and ethnicity and diagnosis period and stratified by cancer site are shown in the Figure.Among patients with endometrial cancer, White and Black women were adequately represented or overrepresented (PPRs Ն1.1) in clinical trials in both time periods, with a slight decline in representation among Black women between the 2 time periods (2004-2011, PPR = 1.4; 2012-2019, PPR = 1.1).Asian and Hispanic women were inadequately represented during both time periods (PPRs Յ 0.5).Among patients with ovarian cancer, White women were overrepresented during both time periods, whereas Asian, Black, and Hispanic women were underrepresented during both periods (PPRs Յ 0.6).For cervical cancer, Black and White women were either overrepresented or adequately represented during both time periods, whereas Asian and Hispanic women were underrepresented.Further details of the PPRs are shown in eTable 2 in Supplement 1.

Figure .
Figure.Participation-to-Prevalence Ratios for Women With Gynecologic Cancer by Diagnosis Period and Cancer Site 8 to 1.2 indicate adequate representation in clinical trials, and PPRs greater than 1.2 indicate overrepresentation. 15Additional methodological details are presented in the eAppendix in Supplement 1. Statistical analyses were performed using Surveillance, Epidemiology, and End Results *Stat software version 8.4.1.1 (National Cancer Institute) and SAS statistical software version 9.4 (SAS Institute).All P values were 2 sided, with statistical significance set at P < .05.Analyses were performed from February 2 to June 14, 2023.

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Treatment at an academic or research program (OR, 6.26; 95% CI, 2.33-16.84)or an integrated network cancer program (OR, 2.93; 95% CI, 1.07-8.05)was associated with higher clinical trial enrollment odds compared with treatment at community cancer programs.Over the study period, we observed higher clinical trial enrollment, with women who received a diagnosis between 2016 and 2019 being approximately 10 times more likely to be enrolled compared with those who received a diagnosis between 2004 and 2006 (OR, 10.18; 95% CI, 6.32-16.39).Patients with ovarian (OR, 3.70; 95% CI, 2.69-5.08)or cervical (OR, 4.30; 95% CI, 2.76-6.70)cancer in Clinical Trial Enrollment Among Women With Gynecologic Cancer Table.Associations of Epidemiologic, Facility, Tumor, and Treatment Characteristics With Clinical Trial Enrollment Among Women With Gynecologic Cancer

Table .
Associations of Epidemiologic, Facility, Tumor, and Treatment Characteristics With Clinical Trial Enrollment Among Women With Gynecologic Cancer (continued) a ORs and 95% CIs were adjusted for all variables in the table.bInthe National Cancer Database, other race is not specified.
International Classification of Diseases for Oncology-3 Codes Including Gynecologic Cancer Histology Types eAppendix.Supplemental Methods eTable 2. Participation-to-Prevalence Ratios for Women With a Gynecologic Cancer Diagnosis According to Cancer Site and Stratified by Year of Diagnosis eReferences